ToxCast and Tox21: Update 2012 PDF
Preview ToxCast and Tox21: Update 2012
ToxCast and Tox21: Update 2012 Richard Judson U.S. EPA, National Center for Computational Toxicology Office of Research and Development UNCG September 2012 Office of Research and Development The views expressed in this presentation are those of the author and do not necessarily reflect the views or policies of the U.S. EPA The Tox21 Community 2 Tox21 Goals • Identify patterns of compound- induced biological response in order to: − characterize toxicity/disease pathways − facilitate cross-species extrapolation − model low-dose extrapolation • Prioritize compounds for more extensive toxicological evaluation • Develop predictive models for biological response in humans Problem Statement Too many chemicals to test with standard animal-based methods –Cost, time, animal welfare Need for better mechanistic data - Determine human relevance - What is the Mode of Action (MOA) or Adverse Outcome Pathway (AOP)? Office of Research and Development 4 National Center for Computational Toxicology ToxCast / Tox21 Goals • Identify molecular targets or biological pathways linked to toxicity –Chemicals perturbing these can lead to adverse events • Develop assays for these targets or pathways –Assays probe “Molecular Initiating Events” or “Key Events” [MIE / KE] • Develop predictive models: in vitro → in vivo –“Toxicity Signature” –Extend to inform biomarkers or bioindicators for key events • Use signatures: –Prioritize chemicals for targeted testing (“Too Many Chemicals” problem) –Suggest / distinguish possible AOP / MOA for chemicals Office of Research and Development 5 National Center for Computational Toxicology Signature Generation In Vitro Data Predictive Models – “Signatures” In Vivo Data Office of Research and Development 6 National Center for Computational Toxicology ToxCast HTS Assays: >1100 readouts / effects Target Family Assay Provider Biological Response Response Element ACEA cell proliferation and death Transporter Assay Design Apredica cell differentiation Cytokines Attagene viability reporter mitochondrial depolarization Kinases BioSeek morphology reporter protein stabilization Nuclear Receptor CellzDirect conformation reporter oxidative phosphorylation CYP450 / ADME NCGC/Tox21 enzyme reporter reporter gene activation Cholinesterase NHEERL MESC membrane potential reporter gene expression (qNPA) Phosphatases NHEERL NeuroTox binding reporter receptor activity Proteases NHEERL Zebrafish inducible reporter receptor binding XME metabolism NovaScreen GPCRs Odyssey Thera Ion Channels Readout Type Species Tissue Source Detection Technology Single Human Lung Breast Multiplexed qNPA and ELISA Rat Liver Vascular Multiparametric Fluorescence & Luminescence Mouse Skin Kidney Alamar Blue Reduction Zebrafish Cervix Testis Cell Format Arrasyscan / Microscopy Sheep Uterus Brain Reporter gene activation Cell free Boar Intestinal Spleen Spectrophotometry Cell lines Rabbit Bladder Ovary Radioactivity Primary cells Cattle Pancreas Prostate HPLC and HPEC Complex cultures Guinea pig Inflammatory Bone TR-FRET Free-living embryos 7 ToxCast: HTS Data Timelines Set Chemicals Assays Endpts Completion Available ToxCast Phase I 293 ~600 ~1100 2011 Now ToxCast Phase II 767 ~600 ~1100 Fall 2012 Beginning 12/12 E1K (endocrine) 880 ~50 ~120 Fall 2012 Beginning 12/12 Tox21 8,193 ~25 ~50 Ongoing Beginning 12/12 ~600 s y a s s A 0 1000 1800 8,200 Chemicals Office of Research and Development National Center for Computational Toxicology 8 Tox21 qHTS 10K Library NCGC EPA NTP • • Pesticides actives and NTP-studied compounds –Drugs inerts • NTP nominations and –Drug-like • Industrial chemicals related compounds compounds • • Endocrine Disruptor NICEATM/ICCVAM –Active Screening Program validation reference pharmaceutical compounds for regulatory ingredients • OECD Molecular tests Screening Working • Group External collaborators (e.g., Silent Spring • FDA Drug Induced Institute, U.S. Army Public Liver Injury Project Health Command) • Failed Drugs • Formulated mixtures Office of Research and Development National Center for Computational Toxicology Predictive Model Development from ToxCast and Other Data DATABASES ToxCastDB ToxRefDB x in vitro in vivo ASSAY SELECTION Univariate Analysis p-value statistics ASSAY AGGREGATION Condense by gene, gene family, or pathway ASSAY SET REDUCTION Reduce by statistics (e.g. correlation) MULTIVARIATE MODEL LDA Office of Research and Development Model Optimization 11 National Center for Computational Toxicology
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